Method of stabilizing pharmaceutical preparations comprising digestive enzyme mixtures

ABSTRACT

The use of complex lipids, especially lecithin, as additives to stabilize water-soluble pharmaceutical preparations of digestive enzyme mixtures containing lipases and proteases, especially pancreatin-containing digestive enzyme mixtures, which are suitable for preparing aqueous solutions for continuous introduction into the gastrointestinal tract by means of a tube, against a decrease in lipolytic activity under the influence of moisture.

BACKGROUND OF THE INVENTION

The present invention relates to the use of complex lipids as additivesstabilizing against a decrease in lipolytic activity under the influenceof moisture to water-soluble pharmaceutical preparations of digestiveenzyme mixtures which contain protease/lipase mixtures, in particularpancreatin, and which are suitable for preparing aqueous solutions forcontinuous introduction into the gastrointestinal tract by means oftubes. The invention furthermore relates to water-soluble pharmaceuticalpreparations of digestive enzyme mixtures containing lipases andproteases, especially of pancreatin-containing digestive enzymemixtures, which are stabilized by complex lipids against a decrease inlipolytic activity under the influence of moisture, and which aresuitable for preparing aqueous solutions which can be introduced intothe gastrointestinal tract of mammals or humans by means of a tube.

A deficiency of digestive enzymes may occur in mammals, especiallyhumans, for example caused by a pathological change in the pancreasresulting from chronic pancreatitis, digestive insufficiency afterstomach operations, hepatic or biliary disorders. It is already knownthat deficiency manifestations of these types can be treated byadministration of non-endogenous pancreatin-containing digestive enzymemixtures such as, for example, pancreatic enzymes, especiallypancreatin, which may optionally also contain added lipases. Thepancreatic enzymes are normally administered orally in the form of solidpreparations. In order for the administered enzyme mixtures taken orallynot to undergo unwanted irreversible denaturation in the stomach bygastric acid and proteolytic enzymes, such as pepsin, present therein,it is necessary to provide the enzyme mixtures with a coating resistantto gastric fluid. A coating of this type permits the intact enzymemixtures to pass through the stomach to their site of action, theduodenum, where the protective layer is degraded by the neutral toslightly alkaline conditions prevailing therein, and the enzymes arereleased. Like the endogenous pancreatic enzymes of the healthy person,the orally administered enzymes are able to display their enzymaticeffects, in particular amylolytic, lipolytic and proteolytic activities,there.

Solid pancreatin formulations of this type which can be coated with afilm resistant to gastric fluid and are in the form of micropellets aredescribed, for example, in Bodecker et al., U.S. Pat. No. 5,378,462 (=DE4,227,385), the disclosure of which is incorporated herein by reference.

For patients with digestive insufficiency, in particular patientsconfined to bed with prolonged digestive insufficiency such as, forexample, chronic pancreatic insufficiency, it would be desirable toadminister non-endogenous digestive enzymes also over a lengthy periodin liquid form, for example by continuous administration by means of atube, in place of solid dosage forms.

It has not heretofore been possible to provide liquid dosage forms ofpancreatin-containing digestive enzyme mixtures, in particular ofpancreatin, because liquid aqueous preparations of such enzyme mixturesare not stable over a lengthy period. It has been found, in particular,that the activity of the lipases present in the mixture decreasesrapidly in the presence of water due to proteolytic attack by theproteases which are likewise present in the mixture, such as trypsin orchymotrypsin. Thus, there may be substantial loss of lipase activity inaqueous pancreatin preparations within a very short time depending onthe external conditions (temperature, pH).

In order to be suitable for continuous introduction into thegastrointestinal tract by administration by means of a tube, aqueoussolutions of digestive enzyme mixtures containing lipases and proteases,in particular of pancreatin-containing digestive enzyme mixtures, mustbe stable for a period of several hours, for example 8 hours. Inparticular, no particles blocking the tube must be produced or presentin the solutions. An essential requirement for solutions of this type isthat an activity of all the digestive enzymes present therein which isas high and as constant as possible is maintained throughout theadministration period. It is furthermore necessary for solutionssuitable for continuous gastrointestinal administration that they arefree of microbe growth, that is to say can be provided for examplepreserved against microbe growth, preferably sterile.

SUMMARY OF THE INVENTION

It was therefore an aim of the invention to provide water-solublepharmaceutical preparations of digestive enzyme mixtures which containlipases and proteases, are stabilized against loss of lipolytic activityunder the influence of moisture, and remain stable dissolved in aqueousmedium over an extended period of time.

These and other aims of the invention have been achieved by providing amethod of stabilizing a water-soluble pharmaceutical preparationcomprising a lypolytic mixture of digestive enzymes selected from thegroup consisting of lipases and proteases, against a decrease inlipolytic activity under the influence of moisture, the pharmaceuticalpreparation being suitable for preparing an aqueous solution forcontinuous introduction through a tube into the gastrointestinal tractof a patient, the method comprising incorporating into thepharmaceutical preparation an effective lypolytic activity stabilizingamount of at least one complex lipid additive.

In accordance with another aspect of the invention, the aims have beenrealized by providing a water-soluble pharmaceutical preparationsuitable for preparing an aqueous solution for continuous introductionthrough a tube into the gastrointestinal tract of a patient, thepharmaceutical preparation comprising a mixture of digestive enzymesselected from lipases and proteases, and further comprising an amount ofat least one complex lipid sufficient to stabilize the digestive enzymemixture against a decrease in lipolytic activity under the influence ofmoisture.

In yet another preferred aspect of the invention, the aims are achievedby providing a kit for preparing an aqueous solution of a digestiveenzyme mixture suitable for continuous introduction through a tube intothe gastrointestinal tract of a patient, said digestive enzyme mixturebeing stabilized against a decrease in lipolytic activity and free ofmicrobe growth, the kit comprising (a) a water-soluble, solidpharmaceutical preparation comprising a mixture of digestive enzymesselected from lipases and proteases, said preparation being free ofmicrobe growth; and (b) an amount of an aqueous solvent sufficient forpreparing the aqueous solution, said solvent being free of microbegrowth; and the kit further comprising an amount of at least one complexlipid contained in the pharmaceutical preparation and/or the aqueoussolvent, the amount of the complex lipid being sufficient to stabilizethe aqueous solution, which is to be prepared, against a decrease inlypolytic activity.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

The invention relates to the use of complex lipids as additivesstabilizing against a decrease in lipolytic activity under the influenceof moisture in water-soluble pharmaceutical preparations of digestiveenzyme mixtures which contain lipases and proteases, in particularpancreatin-containing digestive enzyme mixtures, and which are suitablefor preparing aqueous solutions for continuous introduction into thegastrointestinal tract by means of a tube. The invention furthermorerelates to water-soluble pharmaceutical preparations of digestive enzymemixtures which are stabilized in this way. The invention likewiserelates to kits for preparing aqueous solutions of digestive enzymemixtures suitable for continuous administration by tube.

Complex lipids which are suitable according to the invention asstabilizing additives are, as a rule, insoluble in acetone. Theseinclude, in particular, the phosphorus-containing and carbohydrate-freephospholipids, and the carbohydrate-containing andnon-phosphorus-containing glycolipids and mixtures thereof. It isexpedient to use only phospholipids or mixtures containing phospholipidsand glycolipids.

Suitable phospholipids which can be used according to the invention asstabilizing additives to digestive enzyme mixtures containing lipasesand proteases, especially pancreatin-containing digestive enzymemixtures, are, in particular, salts of anions of the general formula I##STR1## in which R¹ denotes hydrogen or an alkanoyl radical with 10-25carbon atoms, whose hydrocarbon radical may optionally contain 1-4double bonds,

R² denotes hydrogen or an alkanoyl radical with 10-25 carbon atoms,whose carbon radical may optionally contain 1-4 double bonds, or, if R¹does not represent hydrogen, can also denote hydrogen,

R³ denotes hydrogen, a lower alkyl group which can be substituted byamino, lower trialkylammonium, a carboxyl group bonded to a carbon atomcarrying an amino functionality, or a hydroxyl-substituted cycloalkylgroup,

R⁴ denotes hydrogen or a hydrocarbon chain with 10-25 carbon atoms,which may optionally contain 1-4 double bonds,

A represents oxygen or NH,

with a physiologically acceptable cation.

Suitable physiologically acceptable cations include ammonium ions,alkali metal or alkaline earth metal cations, preferably sodium,potassium or calcium, and other physiologically acceptable singly ormultiply charged cations. When R³ contains a nitrogen atom, this canform a quaternary ammonium ion which can likewise serve as cation, sothat inner salts with no external charge are formed.

When the radicals R¹ and/or R² in the compounds of the formula Irepresent an alkanoyl radical, this can be straight-chain or branchedand is, as a rule, unbranched and contains 10-25, preferably 16-20,carbon atoms. The alkanoyl radical may optionally contain up to fourdouble bonds. Alkanoyl radicals which may be present are, in particular,radicals of long-chain fatty acids such as nervonic acid, lignocericacid, palmitic acid, palmitoleic acid, stearic acid, oleic acid,linoleic acid, linolenic acid, arachidic acid or arachidonic acid.

Where the substituent R³ denotes or contains a lower alkyl group, thiscan be straight-chain or branched and contain, in particular, 1 to 4,preferably 1 to 2, carbon atoms. Where R³ denotes a hydroxyl-substitutedcycloalkyl group, this can contain 3 to 6 carbon atoms and besubstituted one or more times by hydroxyl. The cycloalkyl grouppreferably contains 5 to 6 carbon atoms, each of which may besubstituted by hydroxyl.

The R³ O group preferably represents hydroxyl or an alkoxy radical whichhas been produced by esterifying a mono- or polyhydric alcohol with thephosphate group, the mono- or polyhydric alcohol being selected from thegroup consisting of aminoethanol, choline, serine, glycerol andmyoinositol.

Where the radical R⁴ represents a hydrocarbon chain, this can bestraight-chain or branched and is, as a rule, unbranched and contains10-25, preferably 12-20, particularly preferably 15, carbon atoms. Thehydrocarbon chain can optionally contain up to 4, preferably 2,particularly preferably 1, double bond.

The radical A can represent oxygen or the NH group.

Suitable and preferred phospholipids include, for example, phosphatidicacid (1,2-diacyl-sn-glycerol-3-phosphoric acid),phosphatidylcholine(1,2-diacyl-sn-glycerol-3-phosphorylcholine),phosphatidylethanolamine(1,2-diacyl-sn-glycerol-3-phosphorylethanolamine),phosphatidylserine(1,2-diacyl-sn-glycerol-3-phosphorylserine) andphosphatidylinositol(1,2-diacyl-sn-glycerol-3-phosphorylinositol) and,in the case where the phospholipids derive from animal sources of originsuch as, for example, chicken egg, also sphingomyelin, and mixtures ofthese compounds. The said 1,2-diacylphospholipids may be partiallyhydrolysed under certain conditions, for example the enzymatic effect ofa phospholipase. Depending on the nature of the phospholipase, in thiscase the radicals R¹, R², R³ or else [R³ OPO₂ ]⁻ in the1,2-diacylphospholipids may be replaced by hydrogen. If at least one ofthe said molecular radicals in each phospholipid molecule is hydrolysed,then so-called lysophospholipids are produced, in particularlysophosphatidylcholine, lysophosphatidylethanolamine,lysophosphatidylinositol, lysophosphatidylserine and lysophosphatidicacid. These lysophospholipids are also suitable as stabilizing additivesto digestive enzyme mixtures containing lipases and proteases, inparticular pancreatin-containing digestive enzyme mixtures, for thepurpose of the invention.

Glycolipids which can be used in particular are so-calledphytoglycolipids, which occur in plants, of the general formula II##STR2## in which R⁵ and R⁶ each, independently of one another,designate an alkanoyl radical with 10-25 carbon atoms, whose hydrocarbonradical may optionally contain 1-4 double bonds, or denotes hydrogen,but where R⁵ and R⁶ cannot both denote hydrogen, and

R⁷ denotes a mono- or disaccharide residue whose saccharide units areselected from the group consisting of D-fructosyl, D-galactosyl,D-glucosyl and D-mannosyl and mixtures thereof.

Where R⁵ and R⁶ in the compounds of the formula II represent an alkanoylradical, this is branched or unbranched and is, as a rule, unbranchedand contains 10-25, preferably 16-20, carbon atoms. The alkanoyl radicalmay optionally contain up to 4 double bonds. Radicals of long-chainfatty acids such as palmitic acid, palmitoleic acid, stearic acid, oleicacid, linoleic acid, linolenic acid or arachidic acid are particularlysuitable as alkanoyl radicals.

The R⁷ radicals represent mono- or disaccharide residues which may becomposed of the sugar molecules D-galactose, D-glucose, D-mannose orD-fructose. The particularly preferred meaning of R⁷ is D-galactose(then the compounds are monogalactosyl-diglycerides, MGDG) ordigalactose (then the compounds are digalactosyldiglycerides, DGDG;1,2-diacyl-[α-D-galactosyl-(1→6)-β-D-galactosyl-(1.fwdarw.3)]-sn-glycerols).

The phospholipids of the general formula I and the glycolipids of thegeneral formula II each have an asymmetric center or center of chiralityon the middle carbon atom in the glycerol basic structure and may havethe R or S configuration. It is possible for the purpose of theinvention to use the individual stereoisomeric forms of the compounds ofthe formula I and/or of the formula II, and the corresponding mixtures.

The lipid mixtures which have proved beneficial for the stabilizationaccording to the invention of the pharmaceutical preparations ofdigestive enzyme mixtures containing lipases and proteases, inparticular pancreatin-containing digestive enzyme mixtures, are thosewhich can be obtained from natural sources and which represent mixturesof various phospholipids and, where appropriate, various glycolipids.Lecithins may be mentioned as preferred examples of such natural lipidmixtures. Sources of such natural lecithins may be, in particular,plants such as soya beans, sunflowers, rapeseed, maize or peanuts andanimals or animal products such as egg yolk or cerebral matter, but alsomicroorganisms. Lecithins of natural origin are generally commerciallyavailable from various suppliers.

Particularly suitable for the purpose of the invention among thelecithins obtained from plants is soya lecithin, especially soyalecithin enriched in phospholipids, such as, for example, soya lecithinwith a content of about 98% of phospholipids. Untreated, non-enrichedplant lecithins as a rule contain a certain proportion ofphytoglycolipids. Lecithins obtained naturally are mixtures of variousphospholipids and, in the case of a plant origin, also glycolipids,whose composition is not uniform, but may vary depending on theirorigin. Thus, besides the constituents already mentioned above, otherphospholipids may also be present in minor amounts. Table 1 serves toillustrate the average compositions of some untreated, non-enrichedcommercially available lecithins of natural origin.

                  TABLE 1                                                         ______________________________________                                        Composition of some lecithins (%)                                                         Soya   Rapeseed Peanut   Egg                                                  lecithin                                                                             lecithin lecithin lecithin                                 ______________________________________                                        Phosphatidylcholine                                                                         22       37       23     73                                     Phosphatidylethanolamine                                                                    23       29        8     17                                     Phosphatidylserine                                                                           2       --       --     --                                     Phosphatidylinositol                                                                        20       14       17     1                                      Phosphatidic acid                                                                            5       --        2     --                                     Sphingomyelin --       --       --     3                                      Phytoglycolipids                                                                            13       20       38     0                                      Other phospholipids                                                                         12       --       12     --                                     ______________________________________                                    

The pharmaceutical preparations stabilized according to the inventionpreferably contain pancreatin-containing digestive enzyme mixtures.

For the purpose of the present invention, pancreatin means pancreatinwhich has been isolated from mammalian pancreas and whose content ofactive proteases has optionally been increased by autolytic cleavage ofthe protease zymogens originally present therein.

It is possible and preferred for the pancreatin-containing digestiveenzyme mixtures in the pharmaceutical preparations stabilized accordingto the invention to comprise pancreatin obtained from mammalianpancreas, in particular porcine pancreatin, which represents a mixtureof various digestive enzymes. Mammalian pancreatin suitable as an aid todigestion for the human diet, in particular pancreatin from pigpancreas, does not always contain lipases in sufficient amounts forhuman needs. It is therefore possible to add to such pancreatin productsadditional lipase, for example obtained from microorganisms. Thepancreatin/lipase mixtures obtained in this way also represent suitableenzyme mixtures.

The proteases in pancreatin isolated from mammals are, if the pancreatinhas not been subjected to further pretreatment, normally mostly in theform of a proteolytically inactive precursor, the zymogens. It maytherefore be expedient for pharmaceutical purposes to subject the crudepancreatin which has been obtained in a known manner by suitableprecipitation processes from pancreas also to a hydrolytic treatment(autolysis). In this treatment, zymogens are converted into activeproteases. This autolytically pretreated pancreatin (abbreviated toF-pancreatin hereinafter) has a particularly high content of activeproteases so that these F-pancreatins are at particular risk with regardto their lipolytic activity. The use according to the invention ofcomplex lipids is particularly suitable for stabilizing the lipolyticactivity in pharmaceutical preparations containing F-pancreatin. It issurprising in this connection that the stabilization of lipase activitydoes not take place by inactivation of the active proteases present inthe mixture, and the enzyme mixtures stabilized in this way thereforedisplay both amylolytic and lipolytic, and proteolytic activity.

The pancreatin-containing digestive enzyme mixtures in thepharmaceutical preparations to be protected according to the inventionmay, besides pancreatin, additionally contain those lipases present inplants or microorganisms. Lipases from microorganisms may be thoseobtained from bacterial or fungus cultures such as molds, for example ofthe Rhizopus strain.

Additional protease constituents which may be added topancreatin-containing digestive enzyme mixtures in the pharmaceuticalpreparations to be protected according to the invention are other animaland plant proteases, and, in particular, proteases which can be obtainedfrom microorganisms such as bacteria or fungus cultures such as molds,for example of the Aspergillus strain.

The lipases which may be present in pancreatin-free digestive enzymemixtures are those from plants or microorganisms. Lipases frommicroorganisms may be those obtained from bacteria or fungus culturessuch as molds, for example of the Rhizopus strain. Suitable proteasespresent in pancreatin-free digestive enzyme mixtures are animal or plantproteases, and, in particular, proteases which can be obtained frommicroorganisms such as bacteria or fungus cultures such as molds, forexample of the Aspergillus strain.

Pharmaceutical preparations according to the invention may, besidesdigestive enzyme mixtures and complex lipids, additionally containwater-soluble pharmaceutical ancillary substances and/or additives.Examples which may be present are vehicles such as carbohydrates, forexample mannitol, or soluble proteins, and preservatives.

Pharmaceutical preparations of pancreatin-containing digestive enzymemixtures for the purpose of the invention may be water-soluble powderswhich contain, besides pancreatin, in particular F-pancreatin, complexlipids in an amount sufficient to stabilize the lipolytic activity underthe influence of moisture, and optionally additionally water-solubleknown ancillary substances and/or additives.

Water-soluble powders can be produced by substantially removingconstituents which are insoluble in water from the enzyme mixtures. Forthis purpose, undissolved solids can be removed from an aqueouspreparation of F-pancreatin by known methods suitable for removingsolids, for example by centrifugation or filtration, and the resultingsolutions can, where appropriate after adding other ancillary substancesand/or additives, be sterilized by known methods, for example bysterilizing filtration. The ingredients in the resulting clear,optionally sterile solutions can then be obtained as solids again byknown drying methods, for example by freeze drying. The preparationsobtained in this way are suitable for preparing solutions which arestable for several hours, for example up to 8 hours, and whereappropriate are free of microbe growth, and which are suitable forcontinuous gastrointestinal administration at a constant rate topatients, for example by tube.

Continuous administration means essentially uninterrupted administrationof the aqueous solutions which contain the pharmaceutical preparationsaccording to the invention and are, where appropriate, sterile over aperiod of from about one hour up to several hours, for example 8 hours,for example overnight. Continuous administration of the solutions canadvantageously take place through tubes introduced into the digestivetract, for example into the stomach or small intestine.

The efficacy of the added lecithins is substantially independent of therelative lipase/protease ratio in the enzyme mixture. Suitable examplesinclude enzyme mixtures in which the lipase/total proteaseratio--measured by the ratio of the respective activities measured inaccordance with the provisions of the "Federation InternationalePharmaceutique" (abbreviated to FIP hereinafter) (see R. Ruyssen and A.Lauwers, Pharmaceutical Enzymes, Scientific Publishing Company, Gent1978, pages 74-82, quoted as "Lauwers" hereinafter) and indicatedhereinafter in relative activity units, abbreviated to FIP-U/g, can befrom about 5:1 to about 30:1.

The addition according to the invention of complex lipids topharmaceutical preparations of digestive enzyme mixtures containinglipases and proteases, in particular pancreatin-containing digestiveenzyme mixtures, in principle brings about a stabilization against adecrease in the lipolytic activity under the influence of moisture.Moisture is intended to mean essentially aqueous moisture which mayextend from a very low moisture content in the digestive enzyme mixturepowder up to an aqueous preparation of this powder.

An addition according to the invention of complex lipids proves to beexpedient even during the obtaining and processing of thepancreatin-containing digestive enzyme mixtures used in thepharmaceutical preparations for stabilizing the lipolytic activityduring such process steps in the preparation or isolation process inwhich inactivation of the lipase may occur, such as, for example, a wettreatment of the enzyme mixture.

The stabilizing effect of the added complex lipids, in particularlecithin, in an aqueous solution of a pharmaceutical preparationcontaining a digestive enzyme mixture also depends, inter alia, on thepH prevailing in the preparation. pH values which have proved beneficialaccording to the invention are in the pH range of 3.5-9.0, preferably inthe range pH 4.0-7.0, particularly preferably in the range pH 5.0-6.5.

To achieve marked stabilization of the lipolytic activity in thewater-soluble pharmaceutical preparations of digestive enzyme mixturesand the aqueous solutions which can be prepared from these preparationsfor administration by tube, it is necessary to add a certain minimumamount of complex lipids. It is normally possible for the digestiveenzyme mixtures used in the preparations according to the invention tohave a lipase content, expressed in activity units, of, for example,2000 to 200,000 FIP-U/g when they contain only lipases from mammalianpancreatic secretion, and from 2000 to 500,000 FIP-U/g when they containlipases from microorganisms either alone or in combination with lipasesfrom pancreas. An amount of at least 1% by weight of complex lipids,based on the amount employed of solid pancreatin-containing digestiveenzyme mixture, for example an amount of from 1 to 10% by weight, isthen suitable for achieving marked stabilization. Addition of largeramounts of complex lipids is likewise possible but causes no furthernoticeable improvement in the stabilization of the lipolytic activity.Thus, addition of at least 1% by weight, preferably 2 to 5% by weight,particularly preferably about 3% by weight, of lecithin is suitable, forexample, for stabilizing mixtures containing pancreatin, or pancreatinand additional lipase, with complex lipids, in particular lecithin.

It is possible with the aid of the use according to the invention ofcomplex lipids to stabilize such aqueous solutions which can be preparedfrom pharmaceutical preparations with pancreatin-containing digestiveenzyme mixtures and which are prone to a rapid decrease in the lipolyticactivity in such a way that the lipolytic activity of the lipasespresent in the mixture decreases only slightly over a lengthy period.Thus, the aqueous solution of an F-pancreatin stabilized by addedlecithin after an incubation time of 8 hours at room temperature shows aremaining lipolytic activity of 85% of the original initial activity.Even after an incubation time of 24 hours, 50% of the initial lipolyticactivity was still detectable in an aqueous F-pancreatin solutionstabilized by complex lipids. By contrast, the lipolytic activity in anon-stabilized comparison solution had fallen to less than 20% of theinitial activity after 8 hours under otherwise identical conditions.

The stabilization according to the invention of water-solublepharmaceutical preparations of digestive enzyme mixtures containinglipases and proteases against a decrease in lipolytic activity inaqueous medium opens up the possibility of continuously supplyingdigestive enzyme mixtures of this type in the form of an aqueoussolution to patients by introduction into the gastrointestinal tract.The aqueous solutions employed for this purpose should, of course, befree of microbe growth, preferably in fact sterile. Solutions free ofmicrobe growth can be, for example, solutions in which the reproductionof microbes capable of self-reproduction is prevented by addition ofpreservatives.

There is provision according to the invention of a kit for preparingaqueous solutions, which are suitable for continuous introduction intothe gastrointestinal tract by means of a tube, are stabilized againstthe decrease in lipolytic activity and are free of microbe growth, ofdigestive enzyme mixtures, characterized in that it contains ascomponents:

a) a water-soluble solid pharmaceutical preparation, which is free ofmicrobe growth, of a digestive enzyme mixture containing lipases andproteases, which may optionally contain an amount of complex lipidswhich is sufficient for stabilization against a decrease in thelipolytic activity of the aqueous solution to be prepared, and

b) an amount, sufficient for preparing the aqueous solution, of anaqueous solvent which is free of microbe growth and which, besideswater, may contain physiologically tolerated salts and ancillarysubstances and, if the solid pharmaceutical preparation mentioned undera) does not contain a sufficient amount of complex lipids forstabilization of the aqueous solution to be prepared against a decreasein the lipolytic activity, additionally contains a sufficient amount ofcomplex lipids for stabilization against a decrease in the lipolyticactivity of the aqueous solution to be prepared.

In particular, the solid preparation a) used in the kit can represent afreeze-dried digestive enzyme mixture which contains lipases andproteases and which optionally contains complex lipids. The digestiveenzyme mixture is preferably a pancreatin-containing digestive enzymemixture.

Aqueous solutions which are free of microbe growth can be obtained byadding known preservatives, for example parabens. Sterile solutionswhich likewise represent solutions free of microbe growth can beobtained by known sterilization methods, for example sterilizingfiltration.

The lipids present in the kit can preferably be present as additionsalready present in the digestive enzyme mixture (component a)). In orderto prepare a powder of the digestive enzyme mixtures which alreadycontains the complex lipids, it is possible, for example, for asolution, which is free of microbe growth where appropriate, of thecomplex lipids to be mixed with a solution, which is free of microbegrowth where appropriate, of the digestive enzyme mixture, andsubsequently dried by known methods, for example freeze-drying. In orderto obtain from this a solution which can be administered by tube, thecomplex lipids and the powder containing the digestive enzyme mixturemust be mixed with the solvent which is likewise present in the kit,where appropriate under conditions with a controlled microbe content orfree of microbes. The complex lipids can, however, also be presentalready dissolved in the solvent (component b)), for example as acolloid. In order to obtain solutions which can be administered by tube,it is necessary in this case to mix the aqueous solution containingcomplex lipids, or the colloid, where appropriate under sterileconditions, with the digestive enzyme mixture (component a)).

EXAMPLES

1. Stabilization of the Lipolytic Activity of Aqueous PancreatinSolutions by Soya Lecithin

In order to determine the different changes in the lipolytic activitywith and without addition of complex lipids in aqueous pancreatinpreparations, corresponding samples were prepared and incubated at 30°C. The time-dependent change in the lipase activities in the incubationsamples was determined by the method of the "Federation InternationalePharmaceutique/European Pharmacopeia" (abbreviated to FIP/Ph.Eur.hereinafter, see Lauwers, pages 74-82). In this standard determinationmethod, the sample to be investigated for lipase activity is allowed toact under hydrolytic conditions on olive oil triglycerides, and theliberated carboxylic acids are titrated against sodium hydroxide to pH9. The lipase activity of the sample is in this case determined bycomparing the rate at which the sample hydrolyses an olive oil emulsionwith the rate at which a suspension of a pancreas reference powderhydrolyses the same substrate under the same conditions.

1.1 Investigation of Lipase Stability Without Added Lecithin

79.35 mg of a water-soluble, freeze-dried F-pancreatin with a lipolyticactivity of 50473 FIP-U/g were dissolved in 4.0 ml of ice-coldextra-pure water (Nanopur™ supplied by Barnstead), the pH was adjustedto 6.2 with 1 N HCl, and the mixture was subsequently made up to 5.0 mlwith extra-pure water. A sample was immediately taken from this mixtureto determine the initial lipolytic activity ("time zero sample"). Theremaining mixture was incubated in a water bath at 30° C. To take asample, the mixture was thoroughly mixed, and the sample was removedwith a suitable pipette and immediately diluted with ice-cold lipasesolvent so that between 0.5 and 1.5 ml of investigation solution with alipolytic activity of 8 to 16 FIP/U were available for the lipasedetermination. The lipase solvent used in accordance with FIP/Ph.Eur.was a solution of 10.0 g of NaCl, 6.06 g oftris(hydroxymethyl)aminomethane (abbreviated to "TRIS" hereinafter) and4.9 g of maleic anhydride in 900 ml of extra-pure water, whose pH wasadjusted to pH 7 with 4 N sodium hydroxide solution and which wassubsequently made up to 1000 ml with extra-pure water.

In order to measure the time course of the lipase activity, furthersamples were removed from the thermostatically temperature controlledmixture after 15, 30, 60, 120 and 180 minutes and the lipase activitytherein was determined, in each case within 30 minutes, by theFIP/Ph.Eur. method (Lauwers, page 78).

The lipase activity measured in the "time zero sample", in units ofFIP-U/ml, was put as 100% value, and the activities measured during thefurther incubation time are related as percentages to this value. Theresults are listed in Table 2.

1.2 Investigation of Lipase Stability with Added Lecithin

To prepare a lecithin solution, 100 mg of soya lecithin (phospholipidcontent about 98% supplied by Roth) were first made into a paste with alittle extra-pure water at room temperature and then made up to 20.0 ml.The mixture was irradiated with ultrasound while stirring for about 2minutes until a homogeneous colloidal solution was obtained. Then 80.0mg of a water-soluble, freeze-dried F-pancreatin with a lipolyticactivity of 54694 FIP-U/gram were dissolved in 4.0 ml of extra-purewater, and the pH in the solution was adjusted to 6.2 with 1 N HCl. 0.4ml of the lecithin solution (2.5% lecithin based on F-pancreatin powderemployed) was added and the mixture was made up, while mixingthoroughly, to 5.0 ml with ice-cold extra-pure water.

The taking of samples and determination of the lipolytic activities ateach of the incubation times took place as described under 1.1. Theresults are listed in Table 2.

                  TABLE 2                                                         ______________________________________                                        Change in lipolytic activities in aqueous pancreatin                          solutions with and without added lecithin                                     Lecithin    % lipolytic activity after t [min]                                pH    added     0      15    30  60    120  180                               ______________________________________                                        6.2   --        100    69    51  41    26   21                                6.2   2.5%      103    93    90  86    80   75                                ______________________________________                                    

2. Stabilization of the Lipolytic Activity of Aqueous PancreatinPreparations over a Period of 8 Hours

Losses of lipolytic activity occur in aqueous pancreatin preparations,depending on various factors such as temperature, pH and proteolyticactivity of the proteases present. The lipase activity can be distinctlystabilized during incubation at 25° C. for 8 hours by adding complexlipids such as lecithin. Hence, in the following test, the lipolyticactivities in aqueous suspensions and solutions of F-pancreatin, in eachcase with and without addition of complex lipids, were compared over aperiod of 8 hours.

2.1 Preparation of the Incubation Mixtures

For the comparison, clear pancreatin solutions and pancreatinsuspensions from F-pancreatin were in each case investigated with andwithout added lecithin.

The following aqueous preparations were prepared:

a) Pancreatin Solution Without Lecithin

77.5 mg of a water-soluble, freeze-dried F-pancreatin powder asdescribed under 1.1 were dissolved in ice-cold extra-pure water,adjusting the pH to 6.2 with 1 N HCl.

b) Pancreatin Solution with Lecithin

81.0 mg of a water-soluble, freeze-dried F-pancreatin powder were, afterthe pH had been adjusted to 6.2, mixed as described under 1.2 with 0.94ml of lecithin solution and made up to 5.0 ml with ice-cold extra-purewater.

c) Pancreatin Suspension Without Lecithin

2.0 g of F-pancreatin were stirred in 100 ml of ice-cold, extra-purewater for 30 minutes. A cloudy suspension was obtained.

d) Pancreatin Suspension with Lecithin

2.0 g of F-pancreatin were mixed with 100 mg of soya lecithin (suppliedby Roth) and stirred in 100 ml of ice-cold extra-pure water for 30minutes. A cloudy suspension was obtained.

2.2 Test Procedure

Samples were taken immediately after their preparation from the ice-coldsolutions and their suspensions prepared as under 2.1 to determine theinitial lipolytic activity ("time zero samples"). The remainder of themixtures was then incubated in test tubes at 25° C. for 8 hours. Duringthis time, further samples were removed after 30 minutes andsubsequently each hour. The taking of the samples, dilution anddetermination of the lipase activity took place as described under 1.1,except that the test temperature was now 25° C.

The lipase activity (indicated in FIP-U/ml) of the "time zero sample"from an incubation mixture was taken as 100% value, and the activitiesmeasured during the further incubation time were related as percentagesto this value. The results are reproduced in Tables 3 and 4 whichfollow.

                                      TABLE 3                                     __________________________________________________________________________    Course of lipase stability over 8 hours in                                    pancreatin solutions with and without lecithin                                            % lipolytic                                                                   activity                                                              % lecithin                                                                            after t [h]                                                       Mixture                                                                           content                                                                             pH                                                                               ##STR3##                                                                            0.5                                                                             1 2 3 4 5 6 7 8                                          __________________________________________________________________________    a)  --    6.2                                                                             100    72                                                                              64                                                                              47                                                                              36                                                                              30                                                                              27                                                                              24                                                                              21                                                                              19                                         b)  5.8   6.2                                                                             100    97                                                                              98                                                                              96                                                                              98                                                                              94                                                                              92                                                                              89                                                                              85                                                                              85                                         __________________________________________________________________________

                                      TABLE 4                                     __________________________________________________________________________    Course of lipase stability over 8 hours in                                    pancreatin suspensions with and without added lecithin                                    % lipolytic                                                                   activity                                                              % lecithin                                                                            after t [h]                                                       Mixture                                                                           content                                                                             pH                                                                               ##STR4##                                                                            0.5                                                                             1 2 3 4 5 6 7 8                                          __________________________________________________________________________    c)  --    7.1                                                                             100    72                                                                              56                                                                              43                                                                              34                                                                              29                                                                              25                                                                              21                                                                              16                                                                              16                                         d)  5     7.1                                                                             100    97                                                                              97                                                                              92                                                                              84                                                                              77                                                                              72                                                                              69                                                                              64                                                                              60                                         __________________________________________________________________________

3. Stabilization of a Microbial Lipase Towards a Microbial Protease byAddition of Complex Lipids

The following test showed that the activity of microbial lipases couldbe stabilized by adding complex lipids even in the presence of activemicrobial proteases. For this purpose, three investigation solutionscontaining microbial lipase, microbial lipase plus microbial protease,and microbial lipase with added lecithin plus microbial protease, wereprepared. The lipolytic activities in these investigation solutions werethen determined and compared with one another in tables.

3.1 Preparation of the Investigation Solutions

The following solutions were prepared:

a) Lipase Solution

245 mg of lipase from Rhizopus oryzae (Lipase 7-AP 15, AmanoPharmaceutical Co., LTD Nagoya, Japan) with an activity of 170,000FIP-U/g were dissolved in 50 ml of ice-cold, 1% strength sodium chloridesolution.

b) Protease Solution

390 mg of Aspergillus protease (Prozyme 6; Amano Pharmaceutical Co., LTDNagoya, Japan) with an activity of 7600 FIP-U/g were dissolved in 25 mlof ice-cold, 1% strength sodium chloride solution.

c) Lecithin Solution

1 g of lecithin (pure soya lecithin phospholipid content about 98%,supplied by Roth) were taken up in 40 ml of extra-pure water("Nanopure™" supplied by Barnstead) and converted into a colloidalsolution with ultrasound while shaking for about 2 minutes.

The following incubation solutions were prepared from these solutions ina total volume of 5 ml in an ice bath:

                  TABLE 5                                                         ______________________________________                                        Incubation solutions for determining                                          the Rhizopus lipase activity                                                  Incubation                                                                              Lipase  Protease   Lecithin                                                                            NaCl                                       solution  solution                                                                              solution   solution                                                                            solution                                   ______________________________________                                        I         3 ml    --         --    2 ml                                       II        3 ml    1 ml       --    1 ml                                       III       3 ml    1 ml       1 ml  --                                         ______________________________________                                    

The pH of all the incubation solutions after preparation was 6.5 at 37°C.

3.2 Test Procedure

Samples were taken immediately after their preparation from the ice-coldincubation solutions I, II and III for determining the initialactivities ("time zero samples"), and the remainder of the threemixtures was incubated in test tubes in a water bath at 37° C.

To take a sample, the mixture was thoroughly mixed, and the sample wasremoved with a suitable pipette and immediately diluted with ice-coldlipase solvent as described under 1.1. Defined amounts were taken fromeach of these sample solutions (identified by "X" in Table 6) anddiluted to 5 ml with 1% strength sodium chloride solution. 0.5 ml ofeach of these investigation solutions were employed in the lipaseactivity assay.

                  TABLE 6                                                         ______________________________________                                        Amounts of sample removed to                                                  prepare the investigation solutions                                           Investigation                                                                            X μl of sample solution removed after t =                       solution   0 min       30 min  60 min                                         ______________________________________                                        I          150         --      160                                            II         160         500     1000                                           III        160         250     250                                            ______________________________________                                    

3.3 Determination of the Rhizopus Lipase Activity

The catalytic activity of Rhizopus lipase was measured by determiningthe amount of free fatty acids formed from an olive oil emulsion in thepresence of 0.025% of sodium taurocholate over a defined period at pH7.0 and 37° C. In order to ensure that all fatty acids were detected, atitration to pH 9.0 was then carried out. A blank determination bytitration of the substrate emulsion served to detect titratablesubstances not produced by the lipase activity.

The Rhizopus lipase activity of an investigation substance wasdetermined by comparing the rate at which a suspension of the substancehydrolysed an olive oil emulsion with the rate at which a suspension ofa Rhizopus lipase reference standard hydrolysed the same olive oilemulsion under the same conditions.

Reagents

1. Water

Extra-pure water "Nanopure™" supplied by Barnstead was used. It isreferred to hereinafter simply as "extra-pure water".

2. Gum Arabic Solution

110 g of gum arabic and 12.5 g of calcium chloride were dissolved withstirring (about 3 hours) in extra-pure water, made up to 1000 ml andcentrifuged. The solution was dispensed into 250 ml plastic vessels andstored at -20° C.

Gum arabic (acacia gum, DAB 10/Ph.Eur.), calcium chloride analyticalgrade

3. Substrate Emulsion

130 ml of olive oil and 400 ml of gum arabic solution (2) wereemulsified in a suitable stirrer at high speed for 15 minutes. Thetemperature was kept below 30° C. At least 90% of the droplets in theemulsion had a diameter of less than 3 μm and none was larger than 10μm. The emulsion was prepared fresh each day. Olive oil (stored in arefrigerator), DAB quality.

4. Sodium Taurocholate Solution 0.5% (m/V)

0.5 g of sodium taurocholate (lipase activating mixture, mixture ofconjugated bile acids including sodium taurocholate) was dissolved andmade up to 100.0 ml in extra-pure water. The solution was made upfreshly each day. Sodium taurocholate (lipase activating mixture), FIP.

5. Sodium Chloride Solution 1% (m/V) in Extra-pure Water

6. Buffer Solution pH 4.5

2 g of sodium chloride and 9.2 g of sodium dihydrogen phosphate weredissolved in about 950 ml of extra-pure water, adjusted to pH 4.5 withhydrochloric acid and made up to 1000 ml with extra-pure water. Sodiumchloride analytical grade, sodium dihydrogen phosphate, NaH₂ PO₄ ×H₂ O.

7. Sodium Hydroxide Solution 0.1 N

Reference Suspension

The Rhizopus lipase reference standard was stirred in buffer solution(6) and diluted with sodium chloride solution (5) until the enzymesolution contained 12 to 18 units of Rhizopus lipase activity FIP-U/ml.For a standard with 55,000 FIP-U per 1 g, 63 mg were dissolved in 20 mlof buffer solution (6) in an ice bath over the course of 15 minutes. 10ml of this solution were diluted with sodium chloride solution (5) to100 ml in the ice bath. 0.5 ml of this solution were employed in theassay.

Rhizopus lipase reference standard FIP (fungi lipase, FIP standard).

Investigation Solutions

Investigation solutions I, II and III were used.

Test Procedure

The endpoint for the pH-Stat titration was adjusted on the autotitratorof a Radiometer "pH-Stat" titration system to pH 7.0. The following wereput in the reaction vessel:

12.0 ml of olive oil emulsion, FIP (3)

6.5 ml of extra-pure water (1)

1.0 ml of sodium taurocholate solution (4)

The mixture was brought to 37.0° C. The pH was adjusted to pH 7.0 with0.1 N sodium hydroxide solution (7). The burette was then set at "0".

The reaction was started by adding 0.5 ml of reference suspension if thereference value was to be measured, or 0.5 ml of investigation solutionif the lipase activity in the investigation solution was to be measured.After 10 minutes, the endpoint for the pH-stat titration was adjusted topH 9.0. When pH 9.0 was reached, (this step took less than 30 seconds),the titration was stopped and the amount of 0.1N sodium hydroxidesolution used was read off.

To determine the blanks, the endpoint of the titration was adjusted topH 9.0 on the titrator immediately for the reference suspension and theinvestigation solution. After manual adjustment of the pH in thereaction mixture to pH 7.0 and after addition of 0.5 ml of referencesuspension or investigation solution, titration to pH 9.0 wasimmediately carried out. The Rhizopus lipase activity was calculated inFIP-U/ml of investigation solution from the read-off amount of 0.1 Nsodium hydroxide solution used.

The initial lipase activities measured in investigation solutions I, IIand III, in units of FIP-U/ml, are put as 100% values. The activitiesmeasured during the following incubation time of 1 hour were then eachrelated as percentages to these initial values and listed in Table 7.

                  TABLE 7                                                         ______________________________________                                        Stabilization of the activity of                                              Rhizopus lipase by soya lecithin                                                              % lipolytic activity after t =                                Investigation solution                                                                          0 min    30 min  60 min                                     ______________________________________                                        I    Lipase solution  100      100   95                                       II   Lipase solution + protease                                                                     100      17     6                                       III  Lipase solution with lecithin +                                                                100      94    84                                            protease                                                                 ______________________________________                                    

4. Example of a Pharmaceutical Preparation

A) 20.0 g of F-pancreatin are taken up in 400 ml of water, and the pH israpidly adjusted to 6.2 by adding 1 N HCl. Extraction is carried outunder these conditions at 4° C. for 1 hour. The clear supernatantcontaining the pancreatin extract is centrifuged at 53,000 g andsubsequently sterilized by filtration through filters with a pore sizeof 2 μm.

B) 1.0 g of soya lecithin (98% phosphatidylcholine) are dissolved in 50ml of water and sterilized in a sealed glass ampoule at 140° C. for 45minutes.

C) 400 ml of the pancreatin extract prepared in A) are mixed with 25 mlof the lecithin solution prepared in B) under sterile conditions and inthe cold. The mixture is freeze-dried, resulting in 16 g of a powderwhich is dispensed in 2.5 g portions under sterile conditions into 100ml infusion bottles.

5. Examples of Kits for Pharmaceutical Use

5.1 Kit 1

A) 40.0 g of F-pancreatin are taken up in 400 ml of water, and the pH israpidly adjusted to 6.2 by adding 1 N HCl. Extraction is carried outunder these conditions at 4° C. for 1 hour. The clear supernatantcontaining the pancreatin extract is centrifuged at 53,000 g andsubsequently sterilized by filtration through filters with a pore sizeof 2 μm. The extract is dispensed in 25 ml portions under sterileconditions into 100 ml infusion bottles and freeze-dried.

B) 2.0 g of soya lecithin (98% phosphatidylcholine) are dissolved in 20ml of water and homogenized with ultrasound. This colloidal solution issterilized in a sealed glass ampoule at 140° C. for 45 minutes. A 12.5ml portion is removed from this, mixed with 1600 ml of sterilized waterand dispensed in 100 ml portions into infusion bottles.

For use, the contents of a bottle of the solid obtained in A) aredissolved in the contents of a bottle of the solution obtained in B).

5.2 Kit 2

A) 40.0 g of F-pancreatin are taken up in 800 ml of water, and the pH israpidly adjusted to 6.2 by adding 1 N HCl. Extraction is carried outunder these conditions at 4° C. for 1 hour. The clear supernatantcontaining the pancreatin extract is centrifuged at 53,000 g, and theprecipitate is discarded.

B) 32.0 g of mannitol are dissolved in 200 ml of water and mixed with800 ml of the pancreatin extract obtained in A), and the combinedsolutions are sterilized by filtration.

C) 5.0 g of soya lecithin (98% phosphatidylcholine) are dissolved in 50ml of water and homogenized with ultrasound. This colloidal solution issterilized in a sealed glass ampoule at 140° C. for 45 minutes.

D) 1000 ml of the pancreatin extract obtained in B) are mixed understerile conditions with 16 ml of the lecithin solution obtained in C),and freeze-dried. The resulting powder is dispensed in 10.0 g portionsinto sterile 200 ml bottles.

E) Deionized water which has been sterilized by filtration is dispensedunder sterile conditions into 200 ml bottles.

For use, the contents of a bottle of the powder obtained in D) aredissolved in the contents of a bottle of the water dispensed in E).

The foregoing description and examples have been set forth merely toillustrate the invention and are not intended to be limiting. Sincemodifications of the disclosed embodiments incorporating the spirit andsubstance of the invention may occur to persons skilled in the art, theinvention should be construed to include everything within the scope ofthe appended claims and equivalents.

What is claimed is:
 1. A method of stabilizing a water-solublepharmaceutical digestive enzyme preparation, comprising:preparing anaqueous solution for continuous administration through a tube into thegastrointestinal tract of a patient comprising a lipolytic andproteolytic mixture of digestive enzymes consisting of lipases andproteases; and incorporating into said aqueous solution an effectivelipolytic activity stabilizing amount of at least one complex lipidcomprising lecithin from at least one of a plant source, egg yolk,cerebral matter and microorganisms, wherein said stabilizing amountprovides an essentially constant lipolytic activity of the digestiveenzymes in the aqueous solution throughout a several hour administrationperiod of said aqueous solution.
 2. The method according to claim 1,wherein the amount of complex lipid additive comprises at least 1% byweight of the digestive enzyme mixture.
 3. The method according to claim1, wherein the digestive enzyme mixture comprises pancreatin.
 4. Themethod according to claim 3, wherein at least a portion of the complexlipid additive is added to the pancreatin during at least one ofisolating the pancreatin from a pancreatin source and processing of thepancreatin prior to incorporating it into the pharmaceuticalpreparation,wherein the pancreatin is stabilized against a decrease inlipolytic activity during process steps associated with wet treatment.5. The method according to claim 3, wherein the mixture of digestiveenzymes comprises pancreatin and at least one lipase selected from thegroup consisting of plant lipases, bacterial lipases and lipases fromfungus cultures.
 6. The method according to claim 1, wherein the plantsource is selected from the group consisting of soya beans, rapeseed,maize, sunflowers, and peanuts.
 7. The method according to claim 6,wherein the plant source is soya beans.
 8. The method according to claim1, wherein said lypolytic and proteolytic mixture further comprisespharmaceutical water-soluble adjuvants.
 9. A water-solublepharmaceutical digestive enzyme preparation suitable for preparing anaqueous solution for continuous administration through a tube into thegastrointestinal tract of a patient, said preparation comprising:alipolytic and proteolytic mixture of digestive enzymes consisting oflipases and proteases; and an amount of at least one complex lipidadditive comprising lecithin from at least one of a plant source, eggyolk, cerebral matter and microorganisms, wherein said amount providesan essentially constant lipolytic activity of the digestive enzymes inan aqueous solution of said pharmaceutical preparation throughout aseveral hour period.
 10. The pharmaceutical preparation according toclaim 9, wherein the amount of complex lipid is sufficient to stabilizethe lipolytic activity of an aqueous solution of the preparation so thatthe initial lipolytic activity of the solution decreases by not morethan 20% over a period of 8 hours.
 11. The pharmaceutical preparationaccording to claim 10, wherein the amount of complex lipid is sufficientto stabilize the lypolytic activity of the solution so that the initiallipolytic activity of the solution decreases by not more than 50% over aperiod of 24 hours.
 12. The pharmaceutical preparation according toclaim 9, wherein the amount of complex lipid comprises from 1 to 10% byweight of the digestive enzyme mixture.
 13. The pharmaceuticalpreparation according to claim 12, wherein the amount of complex lipidcomprises from 2 to 5% by weight of the digestive enzyme mixture. 14.The pharmaceutical preparation according to claim 9, wherein the amountof complex lipid additive comprises at least 1% by weight of thedigestive enzyme mixture.
 15. The pharmaceutical preparation accordingto claim 9, wherein the plant source is selected from the groupconsisting of soybeans, rapeseed, maize, sunflowers and peanuts.
 16. Thepharmaceutical preparation according to claim 9, wherein the lecithin isfrom microorganisms.
 17. The pharmaceutical preparation according claim9, wherein the lecithin is from chicken eggs.
 18. The pharmaceuticalpreparation according to claim 9, wherein the digestive enzyme mixturecomprises pancreatin.
 19. The pharmaceutical preparation according toclaim 18, wherein the pancreatin comprises autolytically pretreatedpancreatin.
 20. The pharmaceutical preparation according to claim 18,wherein the proteases from pancreatin are essentially present aspre-activated proteases.
 21. The pharmaceutical preparation according toclaim 18, wherein the mixture of digestive enzymes comprises pancreatinand at least one lipase selected from the group consisting of plantlipases, bacterial lipases and lipases from fungus cultures.
 22. Thepharmaceutical preparation according to claim 9, wherein the digestiveenzyme mixture comprises lipases from microorganisms selected from thegroup consisting of bacteria and fungus cultures.
 23. The pharmaceuticalpreparation according to claim 9, wherein the digestive enzyme mixturecomprises proteases from microorganisms selected from the groupconsisting of bacteria and fungus cultures.
 24. The pharmaceuticalpreparation according to claim 9, wherein said water-soluble adjuvantsare carbohydrates or proteins.
 25. The pharmaceutical preparationaccording to claim 9, wherein said lypolytic and proteolytic mixturefurther comprises pharmaceutical water-soluble adjuvants.
 26. A kit forpreparing an aqueous solution of a digestive enzyme mixture suitable forcontinuous introduction through a tube into the gastrointestinal tractof a patient, said kit comprising:a water-soluble, solid pharmaceuticalpreparation comprising a mixture of digestive enzymes consisting oflipases and proteases and optionally further comprising pharmaceuticalwater-soluble adjuvants; an amount of aqueous solvent sufficient forpreparing the aqueous solution, said solvent being free of microbegrowth; and an amount of at least one complex lipid additive comprisinglecithin from at least one of a plant source, egg yolk, cerebral matterand microorganisms contained in at least one of said pharmaceuticalpreparation and said aqueous solvent, wherein said amount of saidcomplex lipid additive stabilizes the aqueous solution which is to beprepared throughout a several hour period.
 27. The kit according toclaim 26, wherein said aqueous solvent further comprises physiologicallyacceptable salts and ancillary substances.
 28. The kit according toclaim 26, wherein the complex lipid additive is contained in the solidpharmaceutical preparation.
 29. The kit according to claim 26, whereinthe complex lipid is contained in the aqueous solvent.
 30. The kitaccording to claim 26, wherein part of the complex lipid is contained inthe solid pharmaceutical preparation and the remainder is contained inthe aqueous solvent.
 31. The kit according to claim 26, wherein thesolid pharmaceutical preparation is a freeze-dried mixture of digestiveenzymes selected from lipases and proteases.
 32. The kit according toclaim 31, wherein the freeze-dried mixture further comprises aneffective lypolytic activity stabilizing amount of at least one complexlipid additive.
 33. The kit according to claim 31, wherein thefreeze-dried enzyme mixture comprises pancreatin.